Several related human diseases result from inherited defects in the ability recognize double strand breaks in DNA and in control of cellular responses to these lesions. These diseases include ataxia telangiectasia, ataxia telangiectasia like disorder, and Nijmegen breakage syndrome which can cause immunodeficiency, predisposition to lymphoma and leukemia, neurodegeneration, and developmental delay. Furthermore, affected individuals are extremely sensitive to ionizing radiation or other stresses that cause double strand breaks, which greatly complicates treatments of cancers that arise. The factors that are mutated in these syndromes are at the heart of the mammalian machinery that detects and repairs DNA double strand breaks. The MRN complex is comprised of Mre11, Rad50 and NBS1. MRN rapidly binds to DNA ends at breaks and plays multiple roles in the preparation for final repair by one of several pathways. While engaging in repair processes, MRN also interacts with and activates the protein kinase ATM, which in turn controls cell cycle checkpoints that prevent cells from dividing until DNA is repaired. The ATM gene is mutated in ataxia telangiectasia, Mre11 in ataxia telangiectasia like disorder, and NBS1 or Rad50 in Nijmegen breakage syndrome. We are continuing our studies to understand how MRN and ATM function, with the ultimate goal of improving the diagnoses and treatment of these diseases. Our approaches include studies of cells and animal models with defects in these genes. Because of the broad impact of these diseases and the diverse roles of the factors involved, this work will also provide important insight into general biological processes required for many aspects of human health and disease. These include the development of our immune system, the maintenance of genomic stability, and control of cellular growth. PUBLIC HEALTH RELEVANCE: Understanding how the MRN complex works will give insight into how our immune system develops and functions. Furthermore, we will learn how cells prevent the DNA rearrangements that occur in the immune system from becoming harmful chromosome aberrations that cause leukemias and lymphomas.